This proposal details the development of new, catalytic reaction methodology for the efficient asymmetric synthesis of polyacetate- and polypropionate-derived macrolide antibiotics, It has been documented that drug-resistant bacterial and fungal infections represent a problem of rapidly growing importance. More than simply achieving syntheses of such compounds, the focus of the proposal is on advancing the frontiers of efficiency, waste-minimization and economic viability of such synthetic efforts. The ultimate goal is thus the realization of practicable and practical chemistry that will affect both the discovery and process phases of research into new medicinal agents. This proposal addresses both the continuation and further development of the most promising discoveries made in the previous funding period, as well as exciting new directions only recently initiated. The reactions under study have as their unifying theme tandem reaction methodology. Tandem reactions are inherently more efficient as multiple chemical transformations may be accomplished, and multiple stereogenic centers may be established in a single operation. In this fashion, large segments of the target natural products may be synthesized with unprecedented efficiency employing only readily available and environmentally benign reagents.